Project Summary Age-related Macular Degeneration (AMD) is the leading cause of blindness in US. It affects over 25% of the people by the age 80. An estimated 25 million people are afflicted with AMD worldwide. Neovascular or ?wet? AMD, which affects 10%?15% of AMD patients, is a rapid form of the disease and progresses to blindness if left untreated. Histopathologically, the disease involves lesions in the Bruch's membrane and or retinal pigment epithelium (RPE) with choroidal neovascularization (CNV; abnormal blood vessels growth from choroid into the retina). As a mediator of angiogenesis and vascular permeability, vascular endothelial growth factor (VEGF) plays a key role in the onset of CNV. Current therapy for wet AMD consists of monthly or bimonthly intravitreal administration of anti-VEGF drugs that sequester VEGF-A extracellularly. This therapeutic approach substantially improves near-term prognosis, but prognosis beyond 2 years of treatment is poor, with steady decline in visual acuity observed to 7 years of follow-up in several clinical trials. Long-term rates of fibrosis & geographic atrophy are higher with chronic anti-VEGF therapy than in historic cohorts of AMD patients. More than half of treated eyes show ongoing CNV leakage, fibrotic scarring, and/or geographic atrophy. A significant number of patients receiving anti-VEGF therapy do not experience substantial visual improvement, and a third of treated eyes continue to lose visual acuity and progress to legal blindness. Furthermore, periodic intravitreal injections imposes significant economic burdens on patients and practices as well as potential risks of bleeding, infection, traumatic injury, and retinal detachment. Our goal is to develop a less invasive therapeutic strategy, which improves vision and halts CNV with an acceptable safety profile and presents reduced risk. Using Phase 1 funding support, we established the dose response and efficacy of intravenously administered Flt23k intraceptor on regression of laser-induced CNV in mice; and determined the safety of intravenously administered Flt23k intraceptor nanoparticles in mice. In Phase II, we propose to assess safety in rabbits and the efficacy of this novel AMD therapy in a non-human primate (NHP, African green monkeys) laser induced CNV model under GLP conditions. We will also pursue appropriate regulatory approvals for this transformative approach of treating AMD. The impact of our Phase II project includes identifying a safe and efficacious dose that is feasible for manufacturing under GMP conditions to test in humans in a Phase 1 clinical trial. We will accomplish the following specific aims: Aim 1: To establish pharmacokinetics and safety of intravenously administered Flt23k intraceptor nanoparticles in rabbits using GLP conditions. Aim 2: To establish the efficacy of intravenously administered Flt23k intraceptor nanoparticles on regression of laser-induced CNV in non-human primates.